Although not approved by the FDA for neuropathic pain, many randomized controlled trials have demonstrated the efficacy of tricyclic antidepressants for the treatment of this condition in both depressed and non-depressed individuals. Recently, an evidence-based guideline sponsored by the International Association for the Study of Pain recommends nortriptyline as a first-line medication for neuropathic pain.[5]

The most common side effects include dry mouth, sedation, constipation, and increased appetite, mild blurred vision, tinnitus, often euphoria and mania.[citation needed] An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects.

However, fewer and milder side effects occur with nortriptyline than tertiary tricyclic antidepressants such as imipramine and amitriptyline. For this reason nortriptyline is preferred to other tricyclic antidepressants, particularly with older adults, which also improves compliance.

A study with men has found that treatment with nortriptyline is associated with higher risk of suicidal ideation compared to escitalopram.[6]

Closer monitoring is required for those with a history of cardiovascular disease, stroke, glaucoma, or seizures, as well as in persons with hyperthyroidism or receiving thyroid hormones.

Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation.

The symptoms and the treatment of an overdose are generally the same as for the other tricyclic antidepressants, including serotonin syndrome and adverse cardiac effects. Because tricyclic antidepressants have a relatively narrow therapeutic index, the likelihood of serious overdose (both accidental and intentional) is fairly high. A nortriptyline overdose is considered a medical emergency and frequently results in death.

Nortriptyline is metabolized in the liver by the hepatic enzyme CYP2D6, and genetic variations within the gene coding for this enzyme can affect its metabolism, leading to changes in the concentrations of the drug in the body.[7] Increased concentrations of nortriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy.[8][9][10]

Individuals can be categorized into different types of CYP2D6 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77-92%) are extensive metabolizers,[10] and have "normal" metabolism of nortriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use nortriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.[8][9][10]

The Clinical Pharmacogenetics Implementation Consortium recommends avoiding nortriptyline in persons who are CYP2D6 ultrarapid or poor metabolizers, due to the risk for a lack of efficacy and side effects, respectively. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers. If use of nortriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.[10] The Dutch Pharmacogenetics Working Group recommends reducing the dose of nortriptyline in CYP2D6 poor or intermediate metabolizers, and selecting an alternative drug or increasing the dose in ultrarapid metabolizers.[11]

These effects account for some therapeutic actions as well as for most side effects such as sedation, hypotension, anticholinergic effects, etc.[clarification needed] Nortriptyline may also have a sleep-improving effect due to its affinity for 5HT2A and histaminergic receptors.[14] In the short term; however, nortriptyline may disturb sleep due to its activating effect.

In one study of long-term efficacy, nortriptyline showed a higher relapse rate in comparison with phenelzine in individuals being treated for depression, possibly due to the metabolite 10-hydroxynortriptyline being produced.[15] The authors of a review noted that the nortriptyline group had more episodes prior to treatment.[15]